Tolebrutinib for SPMS granted FDA breakthrough therapy designation
Developer to soon seek therapy's approval in US for nonrelapsing SPMS
The U.S. Food and Drug Administration (FDA) has granted breakthrough therapy designation to Sanofi’s BTK inhibitor candidate tolebrutinib for the treatment of adults with nonrelapsing secondary progressive multiple sclerosis (SPMS).
According to Sanofi, tolebrutinib is the first investigational BTK inhibitor with the ability to reach the brain to receive the FDA’s breakthrough therapy designation — which is designed to accelerate the development and regulatory review of medications intended to treat serious or life-threatening conditions. That status will allow the company to have more frequent meetings with the FDA to discuss tolebrutinib’s development program, and also makes the treatment eligible for rolling and priority review.
Sanofi is now finalizing an application seeking the approval of tolebrutinib in the U.S. for this type of SPMS, and is preparing a similar one in Europe, the company said in a press release. In nonrelapsing SPMS, symptoms gradually worsen over time in the absence of typical relapse activity.
“We look forward to working with the FDA during the regulatory review of this first-of-its-kind medicine in nonrelapsing secondary progressive multiple sclerosis where there are currently no approved treatments available,” said Erik Wallström, MD, PhD, global head of neurology development at Sanofi.
Status awarded based on data from Phase 3 trial testing tolebrutinib
The breakthrough designation and planned applications are all based on data from the Phase 3 HERCULES clinical trial (NCT04411641), which tested tolebrutinib against a placebo in more than 1,100 adults with nonrelapsing SPMS. The participants had not experienced a relapse in the prior two years but had recent disability progression.
The results showed that, after 48 weeks of treatment, tolebrutinib significantly delayed disability progression by 31%, while also doubling the rates of disability improvement compared with a placebo (10% vs. 5%). Participants given the experimental therapy also had a 38% reduction in new or enlarging brain lesions.
Tolebrutinib was generally safe and well tolerated, although 4.1% of patients experienced a significant increase in liver enzymes, a common issue with BTK inhibitors. Most cases of liver enzyme elevations resolved on their own without medical intervention, but one patient required a liver transplant and later died from complications of that transplant.
According to the company, the introduction of more frequent liver monitoring has helped reduce the occurrence of serious liver complications.
“This breakthrough therapy designation demonstrates the potential for tolebrutinib to delay disability progression, a critical unmet need for people living with multiple sclerosis,” Wallström said.
The class of therapies to which Tolebrutinib belongs is known as BTK inhibitors. They target a protein called Bruton’s tyrosine kinase that’s essential for the survival and activation of immune cells involved in MS.
This breakthrough therapy designation demonstrates the potential for tolebrutinib to delay disability progression, a critical unmet need for people living with multiple sclerosis.
In addition to HERCULES, Sanofi’s clinical development program for tolebrutinib included three other Phase 3 trials: the identical GEMINI 1 (NCT04410978) and GEMINI 2 (NCT04410991) studies, which involve people with relapsing forms of multiple sclerosis (MS), and PERSEUS (NCT04458051), testing tolebrutinib in individuals with primary progressive MS.
Recent data from the GEMINI trials showed that tolebrutinib failed to outperform the approved oral therapy Aubagio (teriflunomide) at lowering relapse rates, failing to meet the trials’ main goal. Still, as in HERCULES, tolebrutinib reduced the risk of disability progression and also helped more patients achieve disability improvement compared with a placebo.
PERSEUS is the only trial of the four that’s still ongoing. Top-line data are anticipated for the second half of 2025.
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